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  • 1. Adem, Abdu
    et al.
    Madjid, Nather
    Stiedl, Oliver
    Bonito-Oliva, Alessandra
    Konradsson-Geuken, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Holst, Sarah
    Fisone, Gilberto
    Ögren, Sven Ove
    Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice.2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no 5, p. 616-628, article id S0924-977X(19)30195-6Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR) transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA) task in mice and the ability of typical and atypical antipsychotic drugs (APDs) to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg) dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.

  • 2. Andreou, Dimitrios
    et al.
    Saetre, Peter
    Kähler, Anna K.
    Werge, Thomas
    Andreassen, Ole A.
    Agartz, Ingrid
    Sedvall, Göran C.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Terenius, Lars
    Jönsson, Erik G.
    Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers2011In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, no 9, p. 700-704Article in journal (Refereed)
    Abstract [en]

    The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n=132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.

  • 3.
    Appel, Lieuwe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lassen, Jorgen Buus
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: Dopamine transporter occupancy as measured by PET2014In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, no 2, p. 251-261Article in journal (Refereed)
    Abstract [en]

    Tesofensine (TE) is a novel triple monoannine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [C-11]beta CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A signnoid E-max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.

  • 4.
    Appel, Lieuwe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Geffen, Yona
    Heurling, Kerstin
    Eriksson, Catarina
    Antoni, Gunnar
    Kapur, Shitij
    BL-1020, a novel antipsychotic candidate with GABA-enhancing effects: D2 receptor occupancy study in humans2009In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 19, no 12, p. 841-850Article in journal (Refereed)
    Abstract [en]

    BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to gamma-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D(2)) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [(11)C]raclopride, assessed the extent and duration of D(2) receptor occupancy (D(2) RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D(2) RO. The 32 mg dose of BL-1020 resulted in an average D(2) RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D(2) RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D(2) ROs ranging from 52 to 66% at a steady state.

  • 5. Bahmanyar, Shahram
    et al.
    Sundstrom, Anders
    Kaijser, Magnus
    von Knorring, Anne-Liis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Kieler, Hale
    Pharmacological treatment and demographic characteristics of pediatric patients with Attention Deficit Hyperactivity Disorder, Sweden2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 12, p. 1732-1738Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to describe the pediatric population with ADHD and their pharmacological treatment. Using the Swedish National Patient Register and the Prescribed Drug Register we identified individuals below 19 years of age who were diagnosed or medically treated for ADHD for the first time 2006-2007. The unique patient identifiers were used to link information from the two registers to describe demographic characteristics, hospital care and drug treatments. Logistic regression model estimated the association between age, sex, frequency of hospitalization, diagnosis or treatment for other mental disorders and risk of gap in the treatment. Totally the study included 7931 patients of whom 74% were males. The mean age at first diagnosis was 12 years. Some 84% were medically treated for ADHD and approximately 90% received methylphenidate as the first substance. Combination therapy was rare and the most common combination was methylphenidate and atomoxetine. More than 55% of the patients, which could be followed up for two years after start of treatment, had at least one treatment gap of six months. Older age at diagnosis, lower number of hospitalizations and comorbidity with other mental disorders increased risks of gaps in medication. Approximately one fifth of the patients recorded in the National Patient Register as diagnosed with ADHD did not receive pharmacological treatment. Medication adherence seems to be low, when measured as gaps in treatment.

  • 6.
    Bakalkin, Georgy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The dynorphin/kappa-opioid receptor system: molecular and epigenetic adaptations in emotional circuitry of alcoholics2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, p. S152-S152Article in journal (Other academic)
  • 7. Baldwin, David S
    et al.
    Allgulander, Christer
    Altamura, Alfredo Carlo
    Angst, Jules
    Bandelow, Borwin
    den Boer, Johan
    Boyer, Patrice
    Davies, Simon
    Dell'osso, Bernardo
    Eriksson, Elias
    Fineberg, Naomi
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Herran, Andres
    Maron, Eduard
    Metspalu, Andres
    Nutt, David
    van der Wee, Nic
    Vázquez-Barquero, Jose Luis
    Zohar, Joseph
    Manifesto for a European anxiety disorders research network2010In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, no 6, p. 426-32Article in journal (Refereed)
    Abstract [en]

    Despite the size, burden and costs of anxiety disorders, many patients remain unrecognised, and the effectiveness of evidence-based interventions in routine clinical practice can be disappointing. The European College of Neuropsychopharmacology (ECNP) has established the ECNP Network Initiative (ECNP-NI) to help meet the goal of extending current understanding of the causes of central nervous system disorders, thereby contributing to improvements in clinical outcomes and reducing the associated societal burden. The Anxiety Disorders Research Network (ADRN) has been adopted within the ECNP-NI: this consensus statement summarises its overall aims and objectives.

  • 8. Björkholm, Carl
    et al.
    Marcus, Monica M
    Konradsson-Geuken, Åsa
    Jardemark, Kent
    Svensson, Torgny H
    The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism.2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. 411-417, article id S0924-977X(17)30047-0Article in journal (Refereed)
    Abstract [en]

    Brexpiprazole (Rexulti(®)), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression.

  • 9. Brain, Cecilia
    et al.
    Allerby, Katarina
    Sameby, Birgitta
    Quinlan, Patrick
    Joas, Erik
    Karilampi, Ulla
    Lindström, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Eberhard, Jonas
    Burns, Tom
    Waern, Margda
    Drug attitude and other predictors of medication adherence in schizophrenia: 12 months of electronic monitoring (MEMS (R)) in the Swedish COAST-study2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 12, p. 1754-1762Article in journal (Refereed)
    Abstract [en]

    The aim was to investigate clinical predictors of adherence to antipsychotics. Medication use was electronically monitored with a Medication Event Monitoring System (MEMS (R)) for 12 months in 112 outpatients with schizophrenia and schizophrenia-like psychosis according to DSM-IV. Symptom burden, insight, psychosocial function (PSP) and side effects were rated at baseline. A comprehensive neuropsychological test battery was administered and a global composite score was calculated. The Drug Attitude Inventory (DAI-10) was filled in. A slightly modified DAI-10 version for informants was distributed as a postal questionnaire. Nonadherence (MEMS (R) adherence <= 0.80) was observed in 27%. In univariate regression models low scores on DAI-10 and DAI-10 informant, higher positive symptom burden, poor function, psychiatric side effects and lack of insight predicted non-adherence. No association was observed with global cognitive function. In multivariate regression models, low patient-rated DAI-10 and PSP scores emerged as predictors of non-adherence. A ROC analysis showed that DAI-10 had a moderate ability to correctly identify non-adherent patients (AUC=0.73, p<0.001). At the most "optimal" cut-off of 4, one-third of the adherent would falsely be. identified as non-adherent. A somewhat larger AUC (0.78, p<0.001) was observed when the ROC procedure was applied to the final regression model including DAI-10 and PSP. For the subgroup with informant data, the AUC for the DAI-10 informant version was 0.68 (p=0.021). Non-adherence cannot be properly predicted in the clinical setting on the basis of these instruments alone. The DAI-10 informant questionnaire needs further testing.

  • 10. Brain, Cecilia
    et al.
    Sameby, Birgitta
    Allerby, Katarina
    Lindström, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Eberhard, Jonas
    Burns, Tom
    Waern, Margda
    Twelve months of electronic monitoring (MEMS (R)) in the Swedish COAST-study: A comparison of methods for the measurement of adherence in schizophrenia2014In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, no 2, p. 215-222Article in journal (Refereed)
    Abstract [en]

    The primary aim was to compare objective and subjective measures of adherence in a naturalistic cohort of schizophrenia outpatients over 12 months between October 2008 and June 2011. Antipsychotic medication adherence was monitored in 117 outpatients diagnosed with schizophrenia or schizophrenia-like psychosis according to DSM-IV criteria in a naturalistic prospective study. Adherence was determined by the Medication Event Monitoring System (MEMS (R)), pill count, plasma levels and patient, staff, psychiatrist and close informant ratings. The plasma level adherence measure reflects adherence to medication and to lab visits. Relationships between MEMS (R) adherence and other measures were expressed as a concordance index and kappa (K). Non-adherence (MEMS (R) <= 0.80) was observed in 27% of the patients. MEMS (R) adherence was highly correlated with pill count (concordance= 89% and K=0.72, p < 0.001). Concordance and K were lower for all other adherence measures and very low for the relationship between MEMS (R) adherence and plasma levels (concordance=56% and K=0.05, p=0.217). Adherence measures were also entered into a principal component analysis that yielded three components. MEMS (R) recordings, pill count and informant ratings had their highest loadings in the first component, plasma levels alone in the second and patient, psychiatrist and staff ratings in the third. The strong agreement between MEMS (R) and pill count suggests that structured pill count might be a useful tool to follow adherence in clinical practice. The large discrepancy between MEMS (R) and the adherence measure based on plasma levels needs further study in clinical settings.

  • 11.
    Chatzittofis, A.
    et al.
    Univ Umea, Dept Clin Sci Psychiat, Umea, Sweden.
    Boström, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Öberg, K.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Flanagan, J.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Arver, S.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Jokinen, J.
    Umea Univ, Dept Clin Sci, Umea, Sweden.
    Testosterone, luteinizing hormone levels and methylation status in men with hypersexual disorders2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, p. S135-S135Article in journal (Other academic)
  • 12.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Gulinello, Maria
    Albert Einstein Coll Med, Dept Neurosci, Behav Core Facil, Bronx, NY USA..
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sylven, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sleep duration, depression, and oxytocinergic genotype influence prepulse inhibition of the startle reflex in postpartum women2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, no 4, p. 767-776Article in journal (Refereed)
    Abstract [en]

    The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression.

  • 13.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Influence of catechol-O-methyltransferase Val158Met polymorphism on startle response in the presence of high estradiol levels2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 7, p. 629-635Article in journal (Refereed)
    Abstract [en]

    Introduction: both human and animal studies have shown a somewhat complex COMT-by-sex interaction effect on brain function and dysfunction. A functional variation in the gene coding for the catechol-O-methyltransferase (COMT) enzyme, which metabolizes dopamine and noradrenaline, has been related to executive and emotional functions, and to sex dimorphism. Aim: to investigate if COMT Val158Met genotype influences startle response in pregnant women, given their physiologically elevated estradiol levels. Methods: seventy-three pregnant women were assessed in gestational week 38 for acoustic startle response, measured by electromyography of the blink reflex, during control condition, positive and negative anticipation stimuli, and pleasant and unpleasant image stimuli. A blood sample was taken for measurement of estradiol levels and genetic analysis. Results: the results indicated a COMT Val158Met effect on startle response across all conditions (main effect of genotype, F(2,70=3.58), p=0.033), where Val/Val women displayed higher startle magnitudes than Val/Met carriers (Cohen's d=0.71). No significant difference by genotype was found in affective modulation. The findings also suggested an estrogen dose-dependent effect of COMT Val158Met on startle reflex. Among women with higher pregnancy-induced estradiol levels, Val/Val carriers had markedly higher startle response across conditions than heterozygotes (Cohen's d=1.36; F(4,21=11.07); p=0.003), while this effect was not present in women with estradiol levels under the median concentration. Conclusions: the observed effect of COMT Val158Met by estradiol on overall startle response is likely to be due to a variable noradrenergic transmission depending on COMT activity in a possible interaction with estradiol. 

  • 14.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hellgren, Chorlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Poromaa, Inger Sundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Pregnancy, anxiety symptoms and catecholaminergic genotype are associated with prepulse inhibition of the startle response in women2015In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, p. S216-S216Article in journal (Other academic)
  • 15.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hallman, Jarmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Wallen-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Haplotype tag single-nucleotide polymorphism analysis of the vesicular glutamate transporter 2 gene in severe alcoholism among women2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S397-S397Article in journal (Other academic)
  • 16.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gene-set-based expression and DNA methylation in hypothalamus and pituitary of rats exposed to early life stress and ethanol drinking2014In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, no Suppl. 2, p. S663-Article in journal (Other academic)
  • 17.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Åslund, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nilsson, Kent W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Three-way interaction effect of 5-HTTLPR, BDNF Val66Met, and childhood adversity on depression: A replication study2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 10, p. 1300-1306Article in journal (Refereed)
    Abstract [en]

    Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Västmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R2=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression.

  • 18.
    Daoura, Loudin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Haaker, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Adolescent and adult male Wistar rats exposed to postnatal maternal separation differ in voluntary ethanol intake2010In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, no Suppl. 1, p. S36-Article in journal (Other academic)
  • 19.
    Engel, Jorgen A.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Pharmacol, SE-40530 Gothenburg, Sweden..
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jerlhag, Elisabet
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Pharmacol, SE-40530 Gothenburg, Sweden..
    A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice2015In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, no 12, p. 2364-2371Article in journal (Refereed)
    Abstract [en]

    Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Metenkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leuenkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959's ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GIS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.

  • 20.
    Engman, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Age, sex and NK1 receptors in the human brain: A positron emission tomography study with [C-11]GR2051712012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no 8, p. 562-568Article in journal (Refereed)
    Abstract [en]

    The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n = 9) and women (n = 9) matched for age varying between 20 and 50 years using the highly specific NK1 receptor antagonist [11C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain-related disorders showing age- and sex-related differences in prevalence.

  • 21.
    Evers, Kathinka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Philosophical challenges for neuroethics2008In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 18, no Suppl. 4, p. S202-S202Article in journal (Refereed)
    Abstract [en]

    Neuroethics is an area concerned with the possible benefitsand dangers of modern research on the brain. Researchers inneuroethics have focused mainly on applied neuroethics, suchas ethical issues involved in neuroimaging techniques, cognitiveenhancement, or neuropharmacology (Illes 2006). Another important,less prevalent, scientific approach is fundamental neuroethics:how knowledge of the brain’s functional architecture and itsevolution can deepen our understanding of identity, consciousnessand intentionality, including the development of moral thoughtand judgment (Evers 2008). The relevance of neuroscience tounderstanding moral judgment depends on the theoretical viewthat is taken on the brain. A modern, dynamic view of thebrain may provide a fruitful theoretical framework for neuroethicsthrough its high explanatory value in regard to the evolution andnature of moral judgment under the aspects of subjective evaluation,free will and personal or public responsibility (Evers 2007).Informed materialism is a model based on the notion that all theelementary cellular processes of brain networks are grounded onphysico-chemical mechanisms and adopts an evolutionary viewof consciousness as a biological function of neuronal activities,but describes the brain as an autonomously active, projective andvariable system in which emotions and values are incorporated asnecessary constraints. Dynamic processes of evaluation and theemotional systems involved in their genesis are basic properties ofour brains: we are neurobiologically predisposed to develop thesecomplex and diverse systems of moral and other values enablingus to establish appropriate relationships in our social, cultural andphysical environments.

  • 22.
    Faria, Vanda
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Imaging the placebo response: a neurofunctional review2008In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 18, no 7, p. 473-485Article, review/survey (Refereed)
    Abstract [en]

    An emerging literature has started to document the neuronal changes associated with the placebo phenomenon. This has altered placebo from being considered a nuisance factor in clinical research to a target of scientific investigation per se. This paper reviews the neuroimaging literature on the placebo effect, and illustrates how imaging tools can improve current understanding of brain mechanisms underlying the placebo response. Imaging studies provide evidence of specific, predictable and replicable patterns of neural changes associated with placebo administration. In general, placebo responses seem mediated by "top-down" processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies. Placebo-induced clinical benefits also involve disorder-specific neuronal responses, yielding neurofunctional or neurochemical alterations similar to those produced by pharmacological treatments.

  • 23.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bani, Massimo
    GlaxoSmithKline, Verona, Italy.
    Pich, Emilio Merlo
    GlaxoSmithKline, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Verona, Italy.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, no 11, p. 1775-1783Article in journal (Refereed)
    Abstract [en]

    Abstract Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40 mg), the NK1R antagonist GR205171 (n=6; 5 mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

  • 24.
    Gingnell, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bannbers, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Premenstrual dysphoric disorder and prefrontal reactivity during anticipation of emotional stimuli2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 11, p. 1474-1483Article in journal (Refereed)
    Abstract [en]

    Premenstrual disorder (PMDD) affects around 5% of women in childbearing ages. An increased sensitivity in emotion processing areas of the brain to variations in ovarian steroid levels has been suggested as part of the pathophysiology in PMDD, but prior neuroimaging studies of emotion processing are yet inconclusive. Previous behavioral studies of women with PMDD have, however, reported enhanced luteal phase startle responsivity during emotional anticipation. Here we used functional magnetic resonance imaging (fMRI) to investigate central neural circuitry activity during anticipation of, and exposure to, emotional stimuli across the menstrual cycle in women with and without PMDD. As compared to healthy controls, women with PMDD displayed significantly enhanced reactivity in the prefrontal cortex during anticipation of, but not exposure to, negative emotional stimuli during the luteal phase. In PMDD patients, BOLD reactivity during anticipation or viewing of negative emotional stimuli was not dependent on absolute levels of estradiol or progesterone. However, progesterone levels were positively correlated with emotion-induced reactivity in the dorsolateral prefrontal cortex to positive emotional stimuli. These findings suggest that cortical emotional circuitry reactivity during anticipation is altered in PMDD during the luteal phase, which might be part of the pathophysiology behind the emotional symptoms or lack of emotional control reported by women with PMDD.

  • 25.
    Goodwin, Guy M.
    et al.
    Univ Oxford, Univ Dept Psychiat, Oxford OX3 7JX, England.;Warneford Hosp, Oxford Hlth NHS Trust, Oxford OX3 7JX, England..
    Holmes, Emily A.
    Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden..
    Andersson, Erik
    Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden..
    Browning, Michael
    Univ Oxford, Univ Dept Psychiat, Oxford OX3 7JX, England.;Warneford Hosp, Oxford Hlth NHS Trust, Oxford OX3 7JX, England..
    Jones, Andrew
    Univ Liverpool, Psychol Sci, Bedford St South, Liverpool L697ZA, Merseyside, England..
    Lass-Hennemann, Johanna
    Saarbrucken Univ, Dept Psychol, Div Clin Psychol & Psychotherapy, D-66123 Saarbrucken, Germany..
    Månsson, Kristoffer N.T.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden.;Stockholm Univ, Dept Psychol, SE-10691 Stockholm, Sweden..
    Moessnang, Carolin
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, J5, D-68159 Mannheim, Germany..
    Salemink, Elske
    Univ Amsterdam, Dept Psychol, Nieuwe Achtergracht 129B, Amsterdam, Netherlands..
    Sanchez, Alvaro
    Univ Ghent, Dept Expt Clin & Hlth Psychol, Henri Dunantlaan 2, B-9000 Ghent, Belgium..
    van Zutphen, Linda
    Maastricht Univ, Dept Clin Psychol Sci, Fac Psychol & Neurosci, Univ Singel 40, NL-6229 ER Maastricht, Netherlands..
    Visser, Renee M.
    Univ Cambridge, MRC, Cognit & Brain Sci Unit, 15 Chaucer Rd, Cambridge CB2 7EF, England..
    From neuroscience to evidence based psychological treatments - The promise and the challenge, ECNP March 2016, Nice, France2018In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 28, no 2, p. 317-333Article in journal (Refereed)
    Abstract [en]

    This ECNP meeting was designed to build bridges between different constituencies of mental illness treatment researchers from a range of backgrounds with a specific focus on enhancing the development of novel, evidence based, psychological treatments. In particular we wished to explore the potential for basic neuroscience to support the development of more effective psychological treatments, just as this approach is starting to illuminate the actions of drugs. To fulfil this aim, a selection of clinical psychologists, psychiatrists and neuroscientists were invited to sit at the same table. The starting point of the meeting was the proposition that we know certain psychological treatments work, but we have only an approximate understanding of why they work. The first task in developing a coherent mental health science would therefore be to uncover the mechanisms (at all levels of analysis) of effective psychological treatments. Delineating these mechanisms, a task that will require input from both the clinic and the laboratory, will provide a key foundation for the rational optimisation of psychological treatments. As reviewed in this paper, the speakers at the meeting reviewed recent advances in the understanding of clinical and cognitive psychology, neuroscience, experimental psychopathology, and treatment delivery technology focussed primarily on anxiety disorders and depression. We started by asking three rhetorical questions: What has psychology done for treatment? What has technology done for psychology? What has neuroscience done for psychology? We then addressed how research in five broad research areas could inform the future development of better treatments: Attention, Conditioning, Compulsions and addiction, Emotional Memory, and Reward and emotional bias. Research in all these areas (and more) can be harnessed to neuroscience since psychological therapies are a learning process with a biological basis in the brain. Because current treatment approaches are not fully satisfactory, there is an imperative to understand why not. And when psychological therapies do work we need to understand why this is the case, and how we can improve them. We may be able to improve accessibility to treatment without understanding mechanisms. But for treatment innovation and improvement, mechanistic insights may actually help. Applying neuroscience in this way will become an additional mission for ECNP.

  • 26. Harro, J.
    et al.
    Kiive, E.
    Laas, K.
    Vaht, M.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Veidebaum, T.
    MAOA VNTR genotype, psychiatric vulnerability and life course in a population-representative longitudinal study2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S360-S360Article in journal (Other academic)
  • 27.
    Hellgren, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Backstrom, T.
    Poromaa, Inger Sundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Low serum allopregnanolone is associated with elevated depressive symptoms in late pregnancy2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S228-S228Article in journal (Other academic)
  • 28.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Immunotherapy in Alzheimer's disease - targeting toxic A beta protofibrils2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S143-S143Article in journal (Other academic)
  • 29. Marcus, Monica M
    et al.
    Björkholm, Carl
    Malmerfelt, Anna
    Möller, Annie
    Påhlsson, Ninni
    Konradsson-Geuken, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Feltmann, Kristin
    Jardemark, Kent
    Schilström, Björn
    Svensson, Torgny H
    Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, no 9, p. 1401-11, article id S0924-977X(16)30102-XArticle in journal (Refereed)
    Abstract [en]

    Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

  • 30.
    Mascalzoni, Deborah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Reverse Discrimination For Psychiatric Genetic Studies In Population-Based Biobanks2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. S475-S476Article in journal (Other academic)
  • 31. Nielsen, Rene Ernst
    et al.
    Lindström, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Nielsen, Jimmi
    Levander, Sten
    DAI-10 is as good as DAI-30 in schizophrenia2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no 10, p. 747-750Article in journal (Refereed)
    Abstract [en]

    Drug attitude inventory (DAI-30) is considered to be the best predictor of poor adherence in first-episode schizophrenia. We compared the short version (DAM 0) with DAI-30 in long-term schizophrenia, documented if DAI was associated with poor insight, PANSS and GAF and constructed DAI-10 percentiles. DAI-30 and DAI-10 were homogenous (r = 0.82 and 0.72, respectively) with good test-retest reliability (0.79). The correlation between the DAI versions was high (0.94). Percentile scores of DAI-10 were computed. DAI is an easy-to-use self-report instrument seemingly assessing a unique clinical dimension relevant to non-adherence. DAI-10 might be preferred for its simplicity and good psychometric properties.

  • 32.
    Oreland, Sadia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Damberg, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hyytiä, Petri
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Activator Protein-2alpha and 2beta levels are higher in alcohol-preferring compared to alcohol-avoiding rats.2007In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 17, no 1, p. S60-S61Article in journal (Other academic)
  • 33.
    Oreland, Sadia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Repeated tactile deprivation in rat pups disrupts the proposed protective consequences of short maternal separations2009In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 19, no 1, p. S47-S48Article in journal (Other academic)
  • 34.
    Päären, Aivar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Jonsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    von Knorring, Anne-Liis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Olsson, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Bohman, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Hypomania spectrum disorders from adolescence to adulthood: a 15-year follow-up of a community sample2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S277-S277Article in journal (Other academic)
  • 35. Schwan, Sofie
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    SSRIs, bone mineral density, and risk of fractures: a review2009In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 19, no 10, p. 683-692Article, review/survey (Refereed)
    Abstract [en]

    A possibility for selective serotonin reuptake inhibitors (SSRIs) to increase the risk of bone fracture has been debated during recent years. Proposed causes include an ability for the drugs to reduce bone mineral density (BMD). Experimental data have identified a functional 5-HT system in bone, although its role is unclear. Results from numerous epidemiological studies are heterogeneous and several different associations have been suggested; between depression and low BMD, SSRIs and low BMD, depression and falls, SSRIs and falls, depression and fractures, and SSRIs and fractures. In this paper, we review the available data and discuss the various study results. Based on the current available data, we conclude that it is not possible to determine whether SSRIs may negatively influence bone regulation or are innocent bystanders. It is likely that only a large, prospective, long-term study designed to investigate changes in BMD will be able to answer the question.

  • 36. Skoglund, Charlotte
    et al.
    Brandt, Lena
    D'Onofrio, Brian
    Larsson, Henrik
    Franck, Johan
    Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders.2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, no 11, p. 1144-1152, article id S0924-977X(17)30902-1Article in journal (Refereed)
    Abstract [en]

    Patients with Attention Deficit/Hyperactivity Disorder (ADHD) and comorbid Substance Use Disorders (SUD) are increasingly being treated with central stimulant medication despite limited evidence for its effectiveness. Lack of longitudinal follow-up studies of dosing and adverse effects has resulted in conflicting treatment guidelines. This study aims to explore whether individuals with ADHD and comorbid SUD are treated with higher stimulant doses than individuals with ADHD only, and whether doses increase over time as a sign of tolerance, a core symptom of addiction. Information on methylphenidate doses for 14 314 Swedish adults, including 4870 individuals with comorbid SUD was obtained through linkages of Swedish national registers between 2006 and 2009. Differences in doses between patients with and without SUD were estimated using logistic regression while a linear regression model calculated time trends in mean doses. Individuals with SUD were prescribed higher methylphenidate doses than those without (ORday365; 2.12, 95% CI 1.81-2.47: ORday730 2.65, 95% CI 2.13-3.30). Patients with SUD were, two years after initiating stimulant treatment, prescribed approximately 40% higher doses compared to individuals with ADHD only. The results may suggest a need for increased doses in this population to achieve optimal ADHD symptom control. A tendency towards increasing doses during the first years of treatment, more pronounced in individuals with comorbid SUD, may reflect a reluctance to prescribe adequate doses due to lack of clinical guidelines. Mean doses stabilized after about two years in both groups, which does not lend support to continuously increasing tolerance over time.

  • 37.
    Soda, Takahiro
    et al.
    Univ N Carolina, Chapel Hill, NC USA..
    Crowley, James
    Univ N Carolina, Chapel Hill, NC USA..
    Breen, Gerome
    King Coll London, London, England..
    Bulik, Cynthia
    Univ N Carolina, Chapel Hill, NC USA..
    Collier, Sarah
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Denny, Joshua
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Howell, Kayla
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sullivan, Patrick
    Univ N Carolina, Chapel Hill, NC USA..
    Biovupsych: Electronic Medical Record-Based Identification of Dna Samples for Disorders Under-Represented n The'Pgc2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. S243-S243Article in journal (Other academic)
  • 38. Sundström-Poromaa, Inger
    et al.
    Gingnell, Malin
    Bannbers, Elin
    Wikström, Johan
    Engman, Jonas
    Fredrikson, Mats
    Influence of reproductive hormones on mood and anxiety in women: premenstrual dysphoric disorders2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no S2, p. S139-S139Article in journal (Other academic)
  • 39.
    Titulaer, Joep
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.
    Malmerfelt, Anna
    Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.
    Marcus, Monica M.
    Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.
    Svensson, Torgny H.
    Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden.
    Enhancement of the antipsychotic effect of risperidone by sodium nitroprusside in rats2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no 11, p. 1282-1287Article in journal (Refereed)
    Abstract [en]

    Recently, a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid and sustained antipsychotic effect in treatment-resistant schizophrenia (TRS). Moreover, a single i.p. injection of SNP in rats was found to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in the medial prefrontal cortex (mPFC) brain slices. Here we used the conditioned avoidance response (CAR) test in rats to investigate the antipsychotic-like efficacy of SNP in combination with low-dose risperidone. In addition, we performed microdialysis experiments in freely moving rats to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc). Risperidone caused only 20% suppression of CAR, which is far below the degree of CAR suppression required to predict a significant clinical antipsychotic effect. Addition of a low dose of SNP to risperidone dramatically enhanced the antipsychotic-like effect to a clinically relevant level. SNP significantly enhanced the risperidone-induced dopamine output in the mPFC but not in the NAc. The increased prefrontal dopamine release induced by the drug combination may also improve cognition as indicated by previous preclinical and clinical studies and, furthermore, via enhanced synaptic spine function and morphology in mPFC generate a both rapid and prolonged antipsychotic and pro-cognitive effect. Our results delineate SNP as a promising new treatment option for schizophrenia, including TRS, when added to currently available antipsychotic medication in order to improve efficacy at maintained or even reduced dosage. 

  • 40.
    Wallen-Mackenzie, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arvidsson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Restrepo, Ernesto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Johann, Stefano Pupe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leao, Richardson Naves
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Targeting VGLUT2 in dopamine neurons affects the brain reward system2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S128-S129Article in journal (Other academic)
  • 41.
    Wingård, Louise
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Brandt, Lena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry. Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Kieler, Helle
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Andersen, Morten
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden;Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark.
    Reutfors, Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Monotherapy vs. combination therapy for post mania maintenance treatment: A population based cohort study2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no 6, p. 691-700Article in journal (Refereed)
    Abstract [en]

    In recent years, the use of atypical antipsychotics and combination therapy for relapse prevention in bipolar disorder has increased substantially. However, real-world data on the comparative effectiveness of these treatment options are largely non-existent. We conducted a population-based cohort study, using data from Swedish national registers. All patients aged 18-75 years who were hospitalized for mania 2006-2014 and filled at least one prescription of lithium, valproate, olanzapine, quetiapine, aripiprazole or any combination of these drugs were included, and followed for up to one year after hospital discharge, generating follow-up data from 5 713 hospitalizations. We used Cox proportional hazard regression models to study time to treatment failure for each individual drug and combination therapy, using lithium as comparator. Treatment failure was defined as treatment discontinuation, switch, or rehospitalization, and the results were adjusted for clinical and sociodemographic factors. We found that treatment failure occurred in 85% of cases and that the majority of combination therapies were associated with lower risks of treatment failure compared to monotherapies. Patients combining lithium + valproate + quetiapine had the lowest risk of treatment failure (adjusted HR [AHR] 0.40, 95% CI 0.30-0.54), followed by patients on lithium + valproate + olanzapine (AHR 0.55, 95% CI 0.45-0.68). In contrast, monotherapies with antipsychotics were associated with significantly higher risks of treatment failure compared to single use of lithium. In conclusion, our results support experimental findings, suggesting that combination therapy is more effective than monotherapy after a manic episode.

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